WO2016042565A1 - Extended release 'formulation of metoprolol - Google Patents

Extended release 'formulation of metoprolol Download PDF

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Publication number
WO2016042565A1
WO2016042565A1 PCT/IN2014/000600 IN2014000600W WO2016042565A1 WO 2016042565 A1 WO2016042565 A1 WO 2016042565A1 IN 2014000600 W IN2014000600 W IN 2014000600W WO 2016042565 A1 WO2016042565 A1 WO 2016042565A1
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WO
WIPO (PCT)
Prior art keywords
metoprolol
lubricant
pharmaceutical composition
ready
instamodel
Prior art date
Application number
PCT/IN2014/000600
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French (fr)
Inventor
Suresh Pareek
Original Assignee
Suresh Pareek
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Publication date
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Priority to PCT/IN2014/000600 priority Critical patent/WO2016042565A1/en
Publication of WO2016042565A1 publication Critical patent/WO2016042565A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a dry ready to use modified release dosage fbr- mubuion for Metoprojlol dosage forms and its salts and derivatives thereof, a process for pceparing extended release tablet using 1NSTAMODEL (A43D00051 ,
  • A43D00043 mamrfactuted by Ideal Cures Private Limited Mumbai India thereof also use thereof as additive to animal feeds, foods and food siipplements and also cosmetic and pharmaceutical compositions.
  • Invention also relates to ready-to-use modified release compositions capable of regulating release of Metoprolol at various dosage strength, a process for production, thereof and also use thereof as formulated pharma- , ceutical. compositions.
  • Metoprolol succinate is a betal-selective (cajrdioselective) adrenoceptor blocking agent, for .oral administration, available as extended release tablets.
  • Metoprolol is a potent inhibitor of #-reoeptor mediated effects mainly involving # 1 -adrenorecepiors. Such effecte include ncrt only reduction of exercise-induced tachycardia but also anti- hypertensive and cardiac antianginal and antiarrhythmic cjffects. The in vivo ab; sorption of metoprolol 1$ rapid and complete.
  • the plasma metoprolol levels following administration of extended release metoprolol succinate are characterized by lower peaks, longer time to peak and significantly lower peak to trough vai ⁇ tiom.
  • c lutosic polymers are used in the modified release compositions e.g. HPMC polymer. These polymers extend the release of drug by showing osmosis nature in aqueous conditions, Cellulosic matrix based system work by the swdling-and gelling function i.e. these polymer swell through influx of liquids and a gel like physical structure is formed which provides extended release effect fa- cilitated by diffusion of the Metoprolol.
  • Some patent documents disclosing matrix based systems for modified release of active ingredients include US 4252786, US 4351825 and WO 2008090569.
  • the object of the present invention is to provide a ready-to-use matrix system and method of preparation for Metoprolol extended release or modified, release for- mulation.
  • the present invention provides hydrophilic matrix system based ready, to use technology for Modified or Extended Release.
  • the present invention also provides method for making ready to use
  • Metoprolol modified or extended release formulation involving steps of aqueous granulation, drying, lubrication and punching of tablets.
  • present invention also provides once a day Metoprolol table dosage form-.
  • Extended release or modified release tablet formulation can be in the form of
  • the solid oral dosage form can optionally include one or more pharmaceutically acceptable excipients.
  • 'modified release' is in context of the invention as a way of active drug delivery where the rate of release of the active drug from the composition is not ex- clusively dependent on the concentration of active drug remaining in the dosage form and / or the solubility of the active dnxg in the liquid surrounding the composition, and where the time course with or without respective location of release of active drug from an oral dosage form are chosen to accomplish therapeutic or convenience ob- jectives not offered by conventional dosage forms.
  • active drug is selected from Aceclofenac, its intermediates and derivatives thereof.
  • 'Aceclofenac' is in context of the invention includes its polymorphic forms, the pharmaceutically acceptable salts, including salts esters and pother chemical derivatives or intermediates etc.
  • the solid pharmaceutical composition comprises Ace- clofenac from 1 to 80 w/w % of dosage form.
  • the term 'dosage', 'solid pharmaceutical composition'. may include one or more of tablet, capsule., powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like.
  • the solid pharmaceutical composition also includes multilayer tablets. The solid pharmaceutical compositions are meant for oral administration.
  • tablette includes pharmaceutical compositions of all shapes and sizes, whether coated or uncoated.
  • Lubricant of present invention includes but not limited to talc, magnesium stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.
  • Glidant in the context of the present invention, is taken to mean that an ingredient which enhance product flow by reducing inter-particulate friction.
  • Glidant can be used in present invention includes but not limited to silicon di-oxide, colloidal silicon dioxide and there derivatives thereof. It is available under several brand names like AEROSIL® and CAB-O-SIL®.
  • Solvent' in the context of the present invention, js taken to mean , in- gredient that facilitate mixing of components in wet granulation process.
  • Solvent can be used in present invention includes but not limited to Acetone, ethanol, methylene di chloride, isopropyl alcohol, water or their mixture thereof.
  • the term 'Binder' or 'Binding agent' in the context of the present invention is taken to mean ingredient that facilitate binding of components in wet granulation process.
  • Solvent can be used in present invention includes but not limited to dextrin and their derivatives, maltodextrin, polyvinyl polymers, Polyvinyl pyrrolidone K.30 (PVP K30) and there derivatives thereof.
  • the ready to use composition in accordance with present invention comprise IN- STAMODEL (A43D00045).
  • Ace- clofenac is formulated with ready to use composition to prepare modified release dosage form.
  • different salts, derivatives, polymorphs of Aceclofenac could be combined to achieve ready -to-.use composition to achieve extended or modified release dosage form.
  • Aceclofenac is blended with the ready to use polymer and aqueous granulated further the granulated mixture is compressed to produce a solid formulation.
  • the ingredients are blended to form a uniform powder and then compressed with means generally known to skilled in the art,
  • Aceclofenac and INSTAMODEL are .blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and giidant,- and thereafter compressed to form appropriate dosage form and finally coated.
  • Aceclofenac and INSTAMODEL are blended.together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and giidant, and thereafter compressed to form appropriate dosage form and optionally coated.
  • Another advantage of the present formulation is its robust and reproducible results for extended release dose form without batch to batch variations. Further by using aqueous solvent system for granulation dosage form does not have any residual solvent or hazardous effect found in many organic solvent. based formulations.. ;
  • inventive, dosage form may be prepared by blending Aceclofenac, their derivatives or combination thereof along with ready to use composition. Therefore inventive for- mulation preparation comprise steps as:
  • 'modified release' is in context of the invention as a way of active drug delivery where the rate of release of the active drug from the composition is not ex- clusively dependent on the concentration of active drug remaining in the dosage form and / or the solubility of the active drug in the liquid surrounding the composition, and where the time course with or without respective location of release of active drug from an oral dosage form are chosen to accomplish therapeutic or convenience ob- jectives not offered by conventional dosage forms.
  • active drug is selected from Metoprolol, its intermediates and derivatives thereof.
  • Metoprolol is in context of the invention includes its polymorphic forms-, the pharmaceutically acceptable salts, including salts esters and pother chemical derivatives or intermediates etc.
  • the solid pharmaceutical composition comprises Metoprolol from 1 to 50 w/w % of dosage form.
  • the term 'dosage', 'solid pharmaceutical composition' may include one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like.
  • the solid pharmaceutical composition also includes multilayer tablets.
  • the solid pharmaeeutica.1 compositions are meant for oral administration.
  • tablette includes pharmaceutical compositions of all shapes and sizes, whether coated or uncoated.
  • Lubricant of present invention includes but not limited to talc, magnesium stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.
  • Glidanf in the context of the present invention, is taken to mean that an ingredient which enhance product flow by reducing inter-particulate friction.
  • Glidant can be used in present invention includes but not limited to silicon di-oxide, colloidal silicon dioxide and there derivatives thereof. It is available under several brand names like AEROSIL® and CAB-O-SIL®.
  • Solvent in the context of the present invention, is taken to mean in- gredient that facilitate mixing of components in wet granulation propess.
  • Solvent can be used in present invention includes but not limited to Acetone, ethanol, methylene di chloride, isopropyl alcohol, water or their mixture thereof.
  • extended release solid oral dosage form for Metoprolol can be created with ready to use Instamodel(A43D00051, A43P00043) system and dosage form have advantageous modified release properties.
  • the ready to use composition in accordance with present invention comprise IN- STAMODEL (A43D00051 , A43D00043).
  • Metoprolol. is formulated with ready to use composition to prepare modified release dosage form.
  • different salts, derivatives, v polymorphs of Metoprolol could be combined to achieve ready-to-use composition to * achieve extended or modified release dosage form.
  • Metoprolol is blended with the ready . ⁇ . to use polymer and aqueous granulated further the granulated mixture, is compressed to produce a solid formulation.
  • the ingredients are blended to form a uniform powder and then compressed with means generally known to skilled in the art.
  • Metoprolol and INSTAMODEL are blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and glidant, and thereafter ' compressed to form appropriate dosage form and finally coated. .
  • Metoprolol and INSTAMODEL are blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and glidant, and thereafter compressed to form appropriate dosage form and optionally coated.
  • This system of formulation uses simple and economic polymers hence cost effective to the customer.
  • Another advantage of the present formulation is its robust and reproducible results for extended release dose form without batch to batch variations. Further by using aqueous solvent system for granulation.dosage form does not have any residual solvent or hazardous effect found in many organic solvent based formulations.
  • Inventive dosage form may be prepared by blending Metoprolol, their derivatives or combination thereof along with ready to use composition. Therefore inventive for- mulation preparation comprise steps as. [49]
  • inventive dosage form is prepared by blending ready to use composition (Instamodel A43D00051 , A43D00043), process blending is performed by conventional dry blender or a food processor or 'V-blender' or a similar function device.
  • Metoprolol are processed using aqueous solvent with binder through wet granulation or a similar wets mixing method to generate dosage formulation.
  • Dosage formulation is further dried, sieved and compressed optionally with addition of lubricant, binder, glidant to form modified release oral dosage form.
  • inventive dosage formulations are prepared by blending Metoprolol along with Instamodel. Initially alt components are blended by conventional dry blending in a food processor or 'V-blender' or a similar function device. Other solid oral dosage formulation components like (binders, lu- bricants, glidants, detackifier, excipients can be added to create inventive formulation Further mixture is then processed, granulated and sieved. Obtained sieved granulated fomiulatjon is.then again uniformly mixed. with Instamodel and premeasured amount of the lubricant to improve industrial acceptability and oral dosage compression quality. Subsequently uniform mixed inventive formulation is compressed in standard pharmacopoeial equipment to get a controlled release oral dosage formulation of the correct desired weight and strength.
  • inventive dosage formulations are prepared by blending Metoprolol along with Instamodel. Initially all components are blended by conventional dry blending in a food processor or 'V-blender' or a similar function device. Other solid oral dosage formulation components like binders, lu- bricants, glidants, detackifier, excipients can be added to create inventive formulation. Further mixture is then processed, granulated and sieved. Obtained sieved granulated formulation is then uniformly mixed with premeasured amount of the lubricant to improve industrial acceptability and oral dosage compression quality. Subsequently uniform mixed inventive formulation is compressed in standard pharmacopoeial equipment to get a controlled release oral dosage formulation of the correct desired weight and strength.
  • oral dosage forms produced by inventive composition having human administrable active ingredient is suitable for human use.
  • drug suitable for veterinary purpose formulated in accordance with present composition will be suitable for veterinary use.
  • Metoprolol is formulated in oral dosage form for modified or extended release delivery.
  • Inventive composition comprising 20, 25, 50, 100, 150 mg or 200 mg of Metoprolol in plurality of dosage formulations.
  • Controlled release formulation can have combination of one or more ad- ditional drugs.
  • Suitable APIs that can be used with the present invention include, but are not
  • ahdrenergic blocking agent acetyl-cholin-esterase inhibitor; analgesic or antipyretics; angiotensin modulator; anthelmintic agents; anti anxiety agent; an- tibacterial; antibiotic; anticoagulant; anticonvulsant; antidepressant; antifungal; anti- histamine; antimalarial; antimicrobial agent; antipsychotic agent; Antiviral agents; blood glucose lowering drug; calcium channel modulator; diuretic; erectile dys- function; gastric acid secretion inhibitor; histamine H2-receptor antagonist; inhibitor of' steroid Type II 5[alpha]- reductase including; lipid regulating agents; selective Hl- receptor antagonist; vasodilator; vitamins.
  • Resulting granules are then processed using slugging method and compressing it on 18 x 7.5 mm of capsule shaped punches at 700 mg of average weight and 7- 10 kg/cm2 of hardness. Mill the slug obtained and sift them using 1.0 mm screen. De-slugging is performed on milled formulation using vibratory sifter fitted with #30 mesh screen. Material generated by de-slugged process is further blended with 2.0 kg Instamodel (A43D00043) using vibratory sifter fitted with # 40 mesh sieve for 20 minutes in suitable blender or octagonal blender. [60] Table 1
  • Coating is preformed on dosage form using INSTACOAT Pharma RnD coater (6' pan) at 25 rpm with inlet temperature being 53 °C and bed temperature at 40 °C. coating was done using 1mm nozzle sprayer with peristaltic pump injecting coating suspension at the rate of lml/min. Coated tablets are then dried and packed as per pharmacopoieal guidelines.
  • Metoprolol is prepared using composition as stated in table:- 2 wherein Metoprolol is 4.75 kg and weighed ac- cordingly, subsequently sieved to get uniformly granulated powder through 40 mesh screen. It is noted that other size screen could be used to get similar results.
  • Sieved Metoprolol is blended with 21.75 kg of ready to use instamodel (A43D00051 ) in blender for 20 minutes (e.g. RMG granulator). Further 0.25 kg of Colloidal silicon dioxide and 0.25 kg of magnesium stearate sieved through 40 mesh screen is added to above blended for subsequent 5 minutes.
  • Resulting granules are then processed using slugging method and compressing it on 18 x 7.5 mm of capsule shaped punches at 700 mg of average weight and 7- 10 kg/cm 2 of hardness. Mill the slug obtained and sift them using 1.0 mm screen. De-slugging is performed on milled formulation using vibratory sifter fitted with #30 mesh screen.
  • Coating is preformed on dosage form using INSTACOAT Pharma RnD coater (6 r pan) at 25 rpm with inlet temperature being 53 °C and bed temperature at, 40 "G. coating was done using 1mm nozzle sprayer with peristaltic pump injecting coating suspension at the rate of. lml/min. Coated tablets are then dried and packed as per pharmacopoieal guidelines.
  • the drug dissolved profile of the Reference products and Metoprolol having dose strength of 25 and 50 mg using Instamodel (A43D00051 , A43D00043 ) formulations* are compared.
  • the release exponents for the Reference and formulated Metoprolol is found to be having similar modified release profile indicating a predominantly diffusion based drug release mechanism.

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Abstract

The present invention relates to a dry ready to use modified release dosage formulation for Metoprolol dosage forms and its salts and derivatives thereof, a process for preparing extended release tablet using INSTAMODEL (A43D00051, A43 D00043) manufactured by Ideal Cures Private Limited Mumbai India thereof also use thereof as additive to animal feeds, foods and food supplements and also cosmetic and pharmaceutical compositions. Invention also relates to ready-to-use modified release compositions capable of regulating release of Metoprolol at various dosage strength, a process for production thereof and also use thereof as formulated pharmaceutical compositions.

Description

Description
EXTENDED RELEASETORMULATION OF METOPROLOL
TeduOod Field
[11 The present invention relates to a dry ready to use modified release dosage fbr- mubuion for Metoprojlol dosage forms and its salts and derivatives thereof, a process for pceparing extended release tablet using 1NSTAMODEL (A43D00051 ,
A43D00043) mamrfactuted by Ideal Cures Private Limited Mumbai India thereof also use thereof as additive to animal feeds, foods and food siipplements and also cosmetic and pharmaceutical compositions. Invention also relates to ready-to-use modified release compositions capable of regulating release of Metoprolol at various dosage strength, a process for production, thereof and also use thereof as formulated pharma- , ceutical. compositions.
Background Art
p] Metoprolol succinate is a betal-selective (cajrdioselective) adrenoceptor blocking agent, for .oral administration, available as extended release tablets. Metoprolol is a potent inhibitor of #-reoeptor mediated effects mainly involving # 1 -adrenorecepiors. Such effecte include ncrt only reduction of exercise-induced tachycardia but also anti- hypertensive and cardiac antianginal and antiarrhythmic cjffects. The in vivo ab; sorption of metoprolol 1$ rapid and complete. The plasma metoprolol levels following administration of extended release metoprolol succinate are characterized by lower peaks, longer time to peak and significantly lower peak to trough vai^tiom.
P] The peak plasma levels following once daily administration of modified release metoprolol succinate average one-fourth to one-half (he peak ptatma levels obtained following a corresponding dose of conventional inetoprolol,. administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following adininistration of extended release metoprolol succinate, across the.dosage range of 50 (o 40Q mg once dairy, was 77% relative to the corresponding single or divided doses of conventional metoprolol.
[4] In state of the art modified release compositions are developed to provide relatively constant drug plasma levels and sustained efficacy for longer period of time. In prtnc^le aim of extended and m
dierapeuttc concenbration of the active m the blood stream and maintain its therapeutic concentnrtion.w½out deviat from strength during specified period. US 79768.71, US 5399358 and US 4927640 are prior are.which disclose wnpositions for sustained release<> actrve ingredients.
[5] In state of art various grades of c lutosic polymers are used in the modified release compositions e.g. HPMC polymer. These polymers extend the release of drug by showing osmosis nature in aqueous conditions, Cellulosic matrix based system work by the swdling-and gelling function i.e. these polymer swell through influx of liquids and a gel like physical structure is formed which provides extended release effect fa- cilitated by diffusion of the Metoprolol. Some patent documents disclosing matrix based systems for modified release of active ingredients include US 4252786, US 4351825 and WO 2008090569.
[6] In theory it is known that with high viscosity grade polymer after attaining gelling effect drug release is lower but as time progresses drug release is increased. On the contrary with low viscosity grade polymer after attaining gelling effect drug is released at faster speed due to larger pore sized and concentration of drug decrease as time progresses.
[7] In order to minimize difficulties associated in ratios of polymers, batch to batch variations, formulating, storing and preserving many loose components of differently textured and sized ingredients means have been desired in industry to make ready to use extended release or modified release composition which are convenient to handle.
[8] The object of the present invention is to provide a ready-to-use matrix system and method of preparation for Metoprolol extended release or modified, release for- mulation.
Disclosure of Invention
Summary of Invention
[9] Accordingly, the present invention provides hydrophilic matrix system based ready, to use technology for Modified or Extended Release. Formulation of Metoprolol Hy- drochloride using INSTAMODEL (A43D00051, A43D00043) manufactured by Ideal Cures Private Limited Mumbai India.
[10] Accordingly, the present invention also provides method for making ready to use
Metoprolol modified or extended release formulation, involving steps of aqueous granulation, drying, lubrication and punching of tablets.
[1 1] In another aspect, present invention also provides once a day Metoprolol table dosage form-.
[12] Extended release or modified release tablet formulation can be in the form of
single or multilayer tablets, capsule shaped oral dosage form, caplet, granules, disc, pellets, granules in capsule, mini-tablets in oral dosage form and other possible oral dosage form mean thereof.
[13] In yet another embodiment, the solid oral dosage form can optionally include one or more pharmaceutically acceptable excipients.
[14] The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Detailed Discription
[15] Below description specify various scientific terms unless stated with context, all technical and scientific terms used herein have the same meaning as. commonly un- derstood by one of ordinary skill in the art, to which this invention belongs, Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
Unless stated to the contrary, The feature 'ready-to-use', in the context of the present invention, is taken to mean the property that the composition according to the invention can be used directly for its purposes by the user by simply dispersing it in required quantity of water.
The term 'modified release' is in context of the invention as a way of active drug delivery where the rate of release of the active drug from the composition is not ex- clusively dependent on the concentration of active drug remaining in the dosage form and / or the solubility of the active dnxg in the liquid surrounding the composition, and where the time course with or without respective location of release of active drug from an oral dosage form are chosen to accomplish therapeutic or convenience ob- jectives not offered by conventional dosage forms. For the purpose of invention active drug is selected from Aceclofenac, its intermediates and derivatives thereof.
The term 'Aceclofenac' is in context of the invention includes its polymorphic forms, the pharmaceutically acceptable salts, including salts esters and pother chemical derivatives or intermediates etc. The solid pharmaceutical composition comprises Ace- clofenac from 1 to 80 w/w % of dosage form.
The term 'dosage', 'solid pharmaceutical composition'. may include one or more of tablet, capsule., powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like. The solid pharmaceutical composition also includes multilayer tablets. The solid pharmaceutical compositions are meant for oral administration.
The term 'tablet' includes pharmaceutical compositions of all shapes and sizes, whether coated or uncoated.
• The term 'Lubricant' in the context of the present invention, is taken to mean that an ingredient added to prevent the adhesion of tablet materials to .the punches and dies, reduce inter-particle friction and facilitate the ejection of oral dosage forms from the die cavity. Lubricant of present invention includes but not limited to talc, magnesium stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.
The term 'Glidant' in the context of the present invention, is taken to mean that an ingredient which enhance product flow by reducing inter-particulate friction. Glidant can be used in present invention includes but not limited to silicon di-oxide, colloidal silicon dioxide and there derivatives thereof. It is available under several brand names like AEROSIL® and CAB-O-SIL®.
The term 'Solvent' in the context of the present invention, js taken to mean , in- gredient that facilitate mixing of components in wet granulation process. Solvent can be used in present invention includes but not limited to Acetone, ethanol, methylene di chloride, isopropyl alcohol, water or their mixture thereof. [24] The term 'Binder' or 'Binding agent' in the context of the present invention, is taken to mean ingredient that facilitate binding of components in wet granulation process. Solvent can be used in present invention includes but not limited to dextrin and their derivatives, maltodextrin, polyvinyl polymers, Polyvinyl pyrrolidone K.30 (PVP K30) and there derivatives thereof.
[25] The ready to use polymeric composition Instamodel A43D00045 for extended and modified release formulation was supplied by Ideal Cures Private Limited, Mumbai, www.idealcures.co.in . This product was used to create inventive dosage form having ideal modified release profile for twice a day administration.
[26] According to inventors it was surprisingly found that extended release solid oral dosage form for Aceclofenac can be created with ready to use Instamodel
(A43D00045) system and dosage form have advantageous modified release properties. The ready to use composition in accordance with present invention comprise IN- STAMODEL (A43D00045). In one of the embodiment of present invention Ace- clofenac is formulated with ready to use composition to prepare modified release dosage form. In accordance with present invention different salts, derivatives, polymorphs of Aceclofenac could be combined to achieve ready -to-.use composition to achieve extended or modified release dosage form.
[27] . In a dosage form according to the invention Aceclofenac is blended with the ready to use polymer and aqueous granulated further the granulated mixture is compressed to produce a solid formulation. The ingredients are blended to form a uniform powder and then compressed with means generally known to skilled in the art,
[28] In yet another embodiment of present invention Aceclofenac and INSTAMODEL are .blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and giidant,- and thereafter compressed to form appropriate dosage form and finally coated.
[29] In yet another embodiment of present invention Aceclofenac and INSTAMODEL are blended.together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and giidant, and thereafter compressed to form appropriate dosage form and optionally coated.
[30] . This system of formulation uses simple and economic polymers hence cost
effective to the customer. Another advantage of the present formulation is its robust and reproducible results for extended release dose form without batch to batch variations. Further by using aqueous solvent system for granulation dosage form does not have any residual solvent or hazardous effect found in many organic solvent. based formulations.. ;
[31 ] inventive, dosage form may be prepared by blending Aceclofenac, their derivatives or combination thereof along with ready to use composition. Therefore inventive for- mulation preparation comprise steps as:
[32] Below description specify various scientific terms unless stated with context, all technical and scientific terms used herein have the same meaning as commonly un- derstood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
Unless stated to the contrary, The feature 'ready-to-use', in the context of the present invention, is taken to mean the property that the composition according to the invention can be used directly for its purposes by the user by simply dispersing it in required quantity of water.
The term 'modified release' is in context of the invention as a way of active drug delivery where the rate of release of the active drug from the composition is not ex- clusively dependent on the concentration of active drug remaining in the dosage form and / or the solubility of the active drug in the liquid surrounding the composition, and where the time course with or without respective location of release of active drug from an oral dosage form are chosen to accomplish therapeutic or convenience ob- jectives not offered by conventional dosage forms. For the purpose of invention active drug is selected from Metoprolol, its intermediates and derivatives thereof.
The term 'Metoprolol' is in context of the invention includes its polymorphic forms-, the pharmaceutically acceptable salts, including salts esters and pother chemical derivatives or intermediates etc. The solid pharmaceutical composition comprises Metoprolol from 1 to 50 w/w % of dosage form.
The term 'dosage', 'solid pharmaceutical composition' may include one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like. The solid pharmaceutical composition also includes multilayer tablets. The solid pharmaeeutica.1 compositions are meant for oral administration.
The. term 'tablet' includes pharmaceutical compositions of all shapes and sizes, whether coated or uncoated.
The term 'Lubricant* in the context of the present invention, is taken to mean that an ingredient added to prevent the adhesion of tablet materials to the punches and dies, reduce inter-particle friction and facilitate the ejection of oral dosage forms from the die cavity. Lubricant of present invention includes but not limited to talc, magnesium stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.
The term 'Glidanf in the context of the present invention, is taken to mean that an ingredient which enhance product flow by reducing inter-particulate friction. Glidant can be used in present invention includes but not limited to silicon di-oxide, colloidal silicon dioxide and there derivatives thereof. It is available under several brand names like AEROSIL® and CAB-O-SIL®.
The term 'Solvent' in the context of the present invention, is taken to mean in- gredient that facilitate mixing of components in wet granulation propess. Solvent can be used in present invention includes but not limited to Acetone, ethanol, methylene di chloride, isopropyl alcohol, water or their mixture thereof.
The term 'Binder' or 'Binding agent' in the context of the present invention, is taken to mean ingredient that facilitate binding of components in wet granulation process. Solvent can be used in present invention includes but not limited to polyvinyl polymers, Polyvinyl pyrrolidone K30 (PVP K30) and there derivatives thereof.
The ready to use polymeric composition Instamodel A43D00051, A43D00043 for extended and modified release formulation was supplied by Ideal Cures Private Limited, Mumbai, www.idealcures.co.ih . This product was used to create inventive dosage form having ideal modified release profile for twice a day administration.
According to inventors it was surprisingly found that extended release solid oral dosage form for Metoprolol can be created with ready to use Instamodel(A43D00051, A43P00043) system and dosage form have advantageous modified release properties. The ready to use composition in accordance with present invention comprise IN- STAMODEL (A43D00051 , A43D00043). In one of the embodiment of present invention Metoprolol.is formulated with ready to use composition to prepare modified release dosage form. In accordance with present invention different salts, derivatives, v polymorphs of Metoprolol could be combined to achieve ready-to-use composition to * achieve extended or modified release dosage form.
Ina.dosage.form according to the invention Metoprolol is blended with the ready . ·. to use polymer and aqueous granulated further the granulated mixture, is compressed to produce a solid formulation. The ingredients are blended to form a uniform powder and then compressed with means generally known to skilled in the art.
In yet another embodiment of present invention Metoprolol and INSTAMODEL are blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and glidant, and thereafter ' compressed to form appropriate dosage form and finally coated. .
In yet another embodiment of present invention Metoprolol and INSTAMODEL are blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and glidant, and thereafter compressed to form appropriate dosage form and optionally coated.
This system of formulation uses simple and economic polymers hence cost effective to the customer. Another advantage of the present formulation is its robust and reproducible results for extended release dose form without batch to batch variations. Further by using aqueous solvent system for granulation.dosage form does not have any residual solvent or hazardous effect found in many organic solvent based formulations.
Inventive dosage form may be prepared by blending Metoprolol, their derivatives or combination thereof along with ready to use composition. Therefore inventive for- mulation preparation comprise steps as. [49]
1. Blending of ready to use formulation Instamodel (A43D00051 , A43D00043) with Metoprolol.
2. Thorough mixing to form dry powder
3. Optionally addition of lubricant
4. Slugging of blended powder
5. Deslugging of tablet
6. Milling and Sieving through appropriate size
7. Optionally adding Instamodel again
8. Optionally addition of lubricant
9. Final tablet compression
10. Optional film coating
According to one of the embodiment inventive dosage form is prepared by blending ready to use composition (Instamodel A43D00051 , A43D00043), process blending is performed by conventional dry blender or a food processor or 'V-blender' or a similar function device. In one of the alternative embodiment Metoprolol are processed using aqueous solvent with binder through wet granulation or a similar wets mixing method to generate dosage formulation. Dosage formulation is further dried, sieved and compressed optionally with addition of lubricant, binder, glidant to form modified release oral dosage form.
In one of the embodiment of present invention, inventive dosage formulations are prepared by blending Metoprolol along with Instamodel. Initially alt components are blended by conventional dry blending in a food processor or 'V-blender' or a similar function device. Other solid oral dosage formulation components like (binders, lu- bricants, glidants, detackifier, excipients can be added to create inventive formulation Further mixture is then processed, granulated and sieved. Obtained sieved granulated fomiulatjon is.then again uniformly mixed. with Instamodel and premeasured amount of the lubricant to improve industrial acceptability and oral dosage compression quality. Subsequently uniform mixed inventive formulation is compressed in standard pharmacopoeial equipment to get a controlled release oral dosage formulation of the correct desired weight and strength.
In one of the embodiment of present invention, inventive dosage formulations are prepared by blending Metoprolol along with Instamodel. Initially all components are blended by conventional dry blending in a food processor or 'V-blender' or a similar function device. Other solid oral dosage formulation components like binders, lu- bricants, glidants, detackifier, excipients can be added to create inventive formulation. Further mixture is then processed, granulated and sieved. Obtained sieved granulated formulation is then uniformly mixed with premeasured amount of the lubricant to improve industrial acceptability and oral dosage compression quality. Subsequently uniform mixed inventive formulation is compressed in standard pharmacopoeial equipment to get a controlled release oral dosage formulation of the correct desired weight and strength.
[53] According to one of the main embodiment wherein hardness of tablets.produced is in range of 5 Kg/cm2 to 15 Kg/cm2. In one of the embodiment oral dosage forms produced by inventive composition having human administrable active ingredient is suitable for human use. Alternatively drug suitable for veterinary purpose formulated in accordance with present composition will be suitable for veterinary use.
[54] According to the objective of present invention Metoprolol is formulated in oral dosage form for modified or extended release delivery. Inventive composition comprising 20, 25, 50, 100, 150 mg or 200 mg of Metoprolol in plurality of dosage formulations. Controlled release formulation can have combination of one or more ad- ditional drugs.
[55] Suitable APIs that can be used with the present invention include, but are not
limited to: ahdrenergic blocking agent; acetyl-cholin-esterase inhibitor; analgesic or antipyretics; angiotensin modulator; anthelmintic agents; anti anxiety agent; an- tibacterial; antibiotic; anticoagulant; anticonvulsant; antidepressant; antifungal; anti- histamine; antimalarial; antimicrobial agent; antipsychotic agent; Antiviral agents; blood glucose lowering drug; calcium channel modulator; diuretic; erectile dys- function; gastric acid secretion inhibitor; histamine H2-receptor antagonist; inhibitor of' steroid Type II 5[alpha]- reductase including; lipid regulating agents; selective Hl- receptor antagonist; vasodilator; vitamins.
[56] Following examples are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof.
Mode for Invention
[57] Example 1 .
[58] Preparation of Metoprolol modified release tablets (25 mg)
[59] The dosage formulation for 100,000 ( 17.00 kg.) Tablets of -Metoprolol is prepared using composition as stated in table:- 1 wherein Metoprolol is, 2.37 kg and weighed ac- cordingly, subsequently sieved to get uniformly granulated powder through 40 mesh screen. It is noted that other size screen could be used to get similar results. Sieved Metoprolol. is blended with 12.12 kg of ready to use Instamodel (A43D00043) in blender, far 20 minutes (e.g. RMG granulator). Further 0.1.2 kg of Colloidal silicon dioxide and 0-.12 kg of magnesium stearate sieved through 40 mesh screen is added to above blended for subsequent 5 minutes. Resulting granules are then processed using slugging method and compressing it on 18 x 7.5 mm of capsule shaped punches at 700 mg of average weight and 7- 10 kg/cm2 of hardness. Mill the slug obtained and sift them using 1.0 mm screen. De-slugging is performed on milled formulation using vibratory sifter fitted with #30 mesh screen. Material generated by de-slugged process is further blended with 2.0 kg Instamodel (A43D00043) using vibratory sifter fitted with # 40 mesh sieve for 20 minutes in suitable blender or octagonal blender. [60] Table 1
Figure imgf000010_0001
. To promote efficient tablet punching further 0.12 kg of Colloidal silicon dioxide and 0.12 kg of magnesium stearate sieved through 40 mesh screen is added to above dried blended formulation in blender for subsequent 5 minutes. Final screened granules are compressed using 8.0 mm (for 25 mg strength at 170 mg average weight) circular, standard concave circular punches using Karnavati Tablet Compression M/C-17 Stn. GMP machine at hardness not less than 5-8 kg/cm2. Generated dosage form tablets are then subjected to film coating using Instacoat Universal. Coating composition is weighed in accordance with table 1 and 11% coating suspension is prepared in water with stirrer and mixed for about 45 minutes subsequently it-is passed through 80 mesh screen. Coating is preformed on dosage form using INSTACOAT Pharma RnD coater (6' pan) at 25 rpm with inlet temperature being 53 °C and bed temperature at 40 °C. coating was done using 1mm nozzle sprayer with peristaltic pump injecting coating suspension at the rate of lml/min. Coated tablets are then dried and packed as per pharmacopoieal guidelines.
Example 2
Preparation of Metoprolol modified release tablets (50 mg)
The dosage formulation for 100,000 (27.50 kg) Tablets of Metoprolol is prepared using composition as stated in table:- 2 wherein Metoprolol is 4.75 kg and weighed ac- cordingly, subsequently sieved to get uniformly granulated powder through 40 mesh screen. It is noted that other size screen could be used to get similar results. Sieved Metoprolol is blended with 21.75 kg of ready to use instamodel (A43D00051 ) in blender for 20 minutes (e.g. RMG granulator). Further 0.25 kg of Colloidal silicon dioxide and 0.25 kg of magnesium stearate sieved through 40 mesh screen is added to above blended for subsequent 5 minutes. Resulting granules are then processed using slugging method and compressing it on 18 x 7.5 mm of capsule shaped punches at 700 mg of average weight and 7- 10 kg/cm2 of hardness. Mill the slug obtained and sift them using 1.0 mm screen. De-slugging is performed on milled formulation using vibratory sifter fitted with #30 mesh screen.
Table 2
Figure imgf000011_0001
To promote efficient tablet punching further 0.25 kg of Colloidal silicon dioxide and 0.25 kg. of magnesium stearate sieved through 40 mesh screen is added to above dried blended formulation in blender for subsequent 5 minutes: Final screened granules are compressed using 9.0 mm (for 50 mg strength at 275 mg average weight) circular, standard concave circular punches Kamavati Tablet Compression M/C-17 Stn. GMP machine at hardness not less than 6-10 kg/cm2. Generated dosage form tablets are then subjected to film coating using lnstacoat Universal. Coating composition is weighed in accordance with table 2 coating suspenstion is prepared in water with stirrer and mixed for about 45 minutes subsequently it is passed through 80 mesh screen. Coating is preformed on dosage form using INSTACOAT Pharma RnD coater (6r pan) at 25 rpm with inlet temperature being 53 °C and bed temperature at, 40 "G. coating was done using 1mm nozzle sprayer with peristaltic pump injecting coating suspension at the rate of. lml/min. Coated tablets are then dried and packed as per pharmacopoieal guidelines.
[68] Example 3
[69] Dissolution Profile Evaluation of Metoprolol tablet
[70] Metoprolol dose form dissolution study was performed. Drug dissolution profiles of tablet prepared are measured by USP 35 dissolution test of rotating basket method <71 1>. It is evident from standard state of the art that active ingredient may have its own dissolution testing parameters which can be found in their respective monographs. The active ingredient content for present invention is standardized for sustained release profile is as per table 2:-
[71] Medium: pH 6.8 phosphate buffer 500 ml
[72] Time interval: 1, 4, 8 and 20 hours
[73] Table 2 .
[74]
Figure imgf000012_0002
[75] METOPROLOL (25mg) IN VITRO % DRUG RELEASE USING IN-
STAMODELYA43D00043) DISSOLUTION COMPARISON .
[76]
Figure imgf000012_0001
[77]
Figure imgf000013_0001
[781 IN VITRO COMPARISON OF DlSSOLUTlO N PROFILE (% Drug Release
METOPROLOL SUCCINATE ER TABLETS 50 MG USING INSTAMODEL
Figure imgf000013_0002
[80]
Figure imgf000014_0001
The drug dissolved profile of the Reference products and Metoprolol having dose strength of 25 and 50 mg using Instamodel (A43D00051 , A43D00043 ) formulations* are compared. The release exponents for the Reference and formulated Metoprolol is found to be having similar modified release profile indicating a predominantly diffusion based drug release mechanism.

Claims

Claims
[1] A modified release solid pharmaceutical composition comprising Metoprolol, In- stamodel (A43D00051, A43D00043), binder, lubricant, glidant optionally opacifiers, colorants.
[2] The solid pharmaceutical composition of claim 1, wherein Metoprolol can be in form of salt, polymorphic form, its derivatives or mixture thereof.
[3] The solid pharmaceutical composition of claim 1 , wherein binder is selected from polyvinyl polymers, Polyvinyl pyrrolidone K30 (PVP K30) and like.
[4] The solid pharmaceutical composition of claim 1 , wherein lubricant is selected from talc, magnesium stearate, stearic acid, sodium stearyl fumarate and com- bination thereof.
[5] The solid pharmaceutical composition of claim I , wherein glidant is selected from silicon di-oxide, colloidal silicon dioxide and there derivatives thereof.
[6] A process for preparing Metoprolol tablet according to claim I comprising
a. Blending of ready to use formulation Instamodel with Metoprolol .. b. Thorough mixing to form dry powder
c. Optionally addition of lubricant
d. Slugging of blended powder
e. Deslugging of tablet
f. Milling and Sieving through appropriate size
, g. Optionally adding Instamodel again.
h. Optionally addition of lubricant
j. Final tablet compression
j.. Optional film coating
[7] The solid pharmaceutical composition prepare using process lor preparing
Metoprolol tablet according to claim 1 comprising
a. Blending of ready to use formulation Instamodei with Metoprolol b. Thorough mixing to form dry powder
c. Optionally addition of lubricant
d. Slugging of blended powder
e. Deslugging of tablet
f. Milling and Sieving through appropriate size
g. Optionally adding Instamodel again.
h. Optionally addition of lubricant
i. Final tablet compression
j. Optional film coating
PCT/IN2014/000600 2014-09-16 2014-09-16 Extended release 'formulation of metoprolol WO2016042565A1 (en)

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